TPM3-NTRK1 fusion

Finally, a TPM3::NTRK1 fusion or MAP2K1 deletion were detected in 2 children with systemic JXG who experienced spontaneous disease regression. This study advances the molecular understanding of histiocytic neoplasms and may guide diagnostics and clinical management.

As demonstrated in our case cohort, 100% of cases diagnosed as high-grade follicular-derived thyroid carcinoma had a mutation or fusion that is associated with worse prognosis, has a germline syndrome association requiring further work up, or an actionable mutation. This high yield seen in this cohort for molecular testing in patients with high-grade follicular-derived thyroid carcinoma suggests more routine molecular testing in this population would be a beneficial clinical practice.

Here we report a large cohort of NTRK fusions detected in a broad range of tumor types during routine clinical care in the community setting. The number of unique and novel fusion partners identified highlights the value of RNAbased NGS, and demonstrates that when performed along with DNA NGS, provides a comprehensive assessment of NTRK fusions and actionable gene alterations to inform the routine clinical care of cancer patients.

The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified.

Regarding break-apart FISH, NTRK detection is difficult because of the diversity of signal patterns. Further research is warranted to identify the characteristics of NTRK-fusion CRCs.

In 2020, UK NICE approved a histology-independent TRK-inhibitor drug, larotrectinib, for treatment of such tumours in both children and adults.Methodology: We present the case of a 49-year old female who presented with recurrence of an NTRK1-TPM3 fusion positive cervical sarcoma nine months following primary total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO). The patient was initially referred with a large cervical mass measuring 9cm on imaging...Although four cycles of doxorubicin were administered, the pulmonary masses continued to progress... Excellent durable response and improved survival was achieved. Testing for NTRK should be done and NTRK inhibitors considered for advanced gynaecological sarcomas. Future research will further assess the efficacy of TRK-inhibition therapy as primary, neoadjuvant and adjuvant treatment.

Interestingly, pan-TRK positivity was observed in one case with precursor lesions in both precancerous and cancerous regions, whereas MLH1 loss was restricted to the cancerous region. In summary, an optimized multi-step algorithm using pan-TRK IHC as a screening method was proposed to identify CRC patients harboring NTRK fusions.

There was homozygous deletion of CDKN2A/B, and there were ROS1, TLX3, FAT1, ABL1, MSH2, and PALB2 mutations. The additional genetic alterations in this case may expand the genotypic spectrum of this distinct cohort.

Herein, we present an acquired TPM3-NTRK1 fusion resistant to larotrectinib in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib.Case Presentation: A 48-year-old male with stage IV adenocarcinoma of lung with metastatic disease of bone was initially treated with carboplatin, pemetrexed, and pembrolizumab...Upon progression of disease (PD), systemic therapy regimen was switched to combination of carboplatin, paclitaxel, and bevacizumab...Subsequently, he was started on alectinib 600 mg twice a day given EML 4-ALK fusion mutation [4.8% of variant allele frequency (VAF)] in circulating tumor DNA (ctDNA) NGS assay...We report the case of acquired TPM3-NTRK1 fusion resistant to larotrectinib and acquired ALK L1196M in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib. Further investigations are warranted to explore the mechanism of resistance to ALK TKIs.

"Our results show that kinase fusions (20/30, 67%) and most importantly targetable NTRK1 fusions (7/30, 23%) are frequent in CRCs with dMLH1/BRAFV600Ewt/MLH1ph/RASwt. NGS was the most comprehensive method in finding the fusions, of which a subset can be screened by Idylla or IHC, provided that the result is confirmed by NGS."